Rapid turnover and recurrent structural variation at the 17q21.31 locus in modern and ancient human genomes, and primates

The 17q21.31 locus in humans harbors several complex structural haplotypes including a ∼970kb inversion. Different inversion haplotypes have been associated with susceptibility to microdeletions causing Koolen-de Vries syndrome and variation in fecundity and recombination rates. Here, using 210 haplotype-resolved human genome assemblies and pangenome graph- based approaches we characterize 11 distinct structural haplotypes, several of which have not been previously described. Extending our analyses to a set of haplotype-resolved great-ape genomes, we characterize the structure of a recurrent inversion in chimpanzees which extends an additional 750kb and is ∼2 million years younger than the human inversion. We further determine that gorillas exhibit an independent duplication of the KANSL1 gene, disruption of which in humans is the cause of Koolen-de Vries syndrome. Using short read sequencing data we characterize 17q21.31 haplotype diversity worldwide in ∼5174 individuals from 107 populations finding increased frequencies of KANSL1 duplication-containing haplotypes in both European and South Asian populations as well as 8 double recombination events between inverted and non inverted haplotypes ranging in size from 20-180kb. Finally, using 626 ancient Eurasian human genomes we show haplotypes containing KANSL1 duplications have increased ∼6-fold over the past 12 thousand years in Europe. Together, our results highlight the dynamics, complexity, and recurrent, independent evolution of a medically relevant locus across humans and great apes.